The focus of this research is to define the natural history of human papillomavirus (HPV) infection and cervical neoplasia, particularly cofactors that explain why cervical HPV infection (a common sexually-transmitted agent) persists and progresses uncommonly to high-grade neoplasia. Accompanying prevention research on HPV diagnostics attempts to improve cervical cancer screening, while projects on HPV immunology are on the forefront of worldwide etiologic and preventive vaccine development efforts (see closely associated HPV vaccines project). Several methodologic and long-term projects were completed in FY 2001 and FY 2002, with a resultant recent concentration on data analyses. Extremely strong and prospective associations of risk of high-grade cervical neoplasia were associated with infection with cancer-associated HPV types, based on data from the 20,000-woman Portland cohort study and the 10,000-woman Costa Rican cohort study. Among HPV-infected women, those who smoked were at additionally increased risk, very high viral loads did not imply especially high risk, while certain HLA alleles conferred apparent protection. Adenocarcinoma was shown to have different risk factors than squamous cancers in a series of case-control analyses. Improved cytologic and HPV DNA test strategies were validated as part of the enrollment phase of the Costa Rican cohort and the ASCUS-LSIL Triage Study, a 5,000-woman clinical trial conducted with the Division of Cancer Prevention. Much of the natural history work in the next few years will derive from the follow-up data from these two studies, and ancillary projects among women 45-70 years of age. Serologic projects continue to demonstrate the HPV-type specificity of the new tests based on synthesized virus-like particles now available for major cancer-associated types. Methods research continues on identifying and validating biomarkers of risk of progression given infection in a new study by Dr. Sophia Wang, and of possible protective immunity to HPV infection that might be useful for the proposed Phase 3 prophylactic trial against HPV 16 infection (see associated HPV vaccines project).